Pyrethroid-containing Parasticidal Compositions This invention concerns pyrethroid-containing compositions for controlling ectoparaβties such as lice, keds, mites, ticks, fleas and nuisance fly and endoparasites such as helminths including gut and lungworms which may infest non-human animals. More specifically the invention is concerned with aqueous compositions containing at least one synthetic (light-stable) pyrethroid insecticide and at least one anthelmintic agent.

The present compositions may be provided in a form suitable for subsequent pour-on or spot-on application to the skin or fleece of a non-human animal according to well known techniques. They may, most conveniently, comprise solutions of the active ingredients.

The principal use of the compositions is for simultaneously controlling endoparasites and ectoparasites in sheep and/or cattle. As such, pour-on compositions are provided which can confer dual control, rendering separate treatments for ecto- and endo-parasites unnecessary. Tetramisole, 2,3,5,6 -tetrahydro-ό-phenylimidazo (2,1-b) thiazole and its (L-) laevo iso er levamisole are known to be effective anthelmintic agents. Tetramisole is a racemic mixture of the D- and L- isomers and the activity against helminths has been shown to be derived mainly or almost entirely from levamisole. Tetramisole and levamisole are described in GB-A-1 04348 *

GB-A-1464 552 is concerned with a method of using tetramisole and/or levamisole by application to the skin of an animal. According to the teaching,the salts should be avoided due to reduced efficacy and water is stated tf ~be an ineffective carrier for effecting passage of the active ingredient through the skin, a pre-requisite to helmintic control.

SUBSTITUTE SHEET

Anthelmintic compositions based on conventional organic solvents have caused skin irritation or damage in the treated animal. GB-A-2095107 discloses anthelmintic compositions having reduced skin irritation problems.

S Synthetic pyrethroids as disclosed in GB-A-1413.491 are known to be powerful insecticides suitable for ectoparasite control on non- human animals.

The term "pyrethroid" as used through the description and claims is meant to include one or more compounds including geometrical and 0 stereochemical isomers according to the formula ( I ) :

'5 wherein M is — CO CH c ^/Xl ( II ) ,

5 or — CO — CH

( IV )

.CH

/ \

CH ₃ CH ₃

and wherein X. to X are independently selected from halo,

(C ₁ - C.)-alkyl, halogen-substituted (C ₁ - C -alkyl, and halogen-substituted phenyl;

X _c is - H or halo; R. is H or cyano; and

R is halogen-substituted phenyl.

Particularly preferred compounds are presented in Tables 1 to 3.

TABLE 1

No. X ₁ X ₂ X, X. X- R ₁ trivial name

1 Cl Cl - - H H permethrin

2 CH, CH, - - H H phenothrin

3 Br Br - H CN deltamethrin

4 Cl Cl - H CN c permethrin

5 Cl CF - H CN cyhalothrin

6 Cl __>._ - - P CN flumethrin

7 Cl Cl - P CN cyfluthrin θ CH, CH, - - H CN cyphenothrin

TABLE 2

c : h

/ \

CH, CH_ J 0

^X 1 ^X 2 trivial nan*

^X 3 ^X 4 ^" 5

Br Br Br Br & CN tralomethrln

Cl Cl Br Br H CN tralocythrin

TABLE

M _. - CO - CH - R ( iv )

I ²

CH

/ \ CH_ CH_

*2 trivial name

*5 ^R 1

-^>-cι H CN fβπvalβratβ

Corabinations of known pyrethroid and anthelmintic agent are disclosed in WO-A-84/000 5, GB-A-2 11001 and GB-A-2 117638. Such disclosures are not concerned with aqueous compositions. These prior art compositions rely, exclusively on organic solvents which leads to increased expenditure on raw materials and environmental concerns and possible health hazards for users. As discussed earlier, there is a prejudice against using (i) salt(s) of levamisole and/or tetramisole and (iii) water as a carrier medium, see GB-A-1 464 552. The present invention is bas_ed on the discovery that water- containing pour-on compositions cam be produced by incorporating at least one organic water-miscible cosolvent. Our experimentation has shown an unexpected improvement in anthelmintic skin penetration compared to levamisole or tetramisole free base alone. Furthermore, organic solvent content can be reduced whilst still maintaining acceptable or superior skin tolerance.

According to this invention there is provided a parasiticide! composition, suitable for pour-on application to a non-human animal which comprises: (i) at least one salt of tetramisole and/or levamisole,

(ii) at least one pyrethroid as herein defined, in carrier system comprising (iii) water, (iv) at least one organic water-miscible cosolvent. The composition may include (v) a minor proportion (less than

5O?o by weigjrt) of at least one organic water-immiscible solvent.

Included within the scope of this invention are pour-on or spot-on compositions for controlling endo- and ectoparasites in a non-human animal and methods of controlling such parasites by use of the compositions. The term controlling is used to mean interfering with the development and/or reproduction of the para- site(s). Preferably, the compositions are solutions and they may be prepared by admixture of the relevant ingredients with (v), when present, being added to (iv) before or after addition of (iii). It is preferred to use salt(s) of levamisole, such as acid addition salt(s). As examples thereof levamisole hydrochloride, levamisole phosphate and levamisole citrate and levamisole oleate may be mentioned. The most preferred salt is levamisole hydrochloride.

As examples of preferred pyrethroids one or more of permethrin, cypermethrin, cyholothrin or decamethrin may be employed. It is more preferred to use permethrin and most preferred to use permethrin in high-cis form. Permethrin contains cis- and trans-isomers aryl it has been found that the cis-isomer is the more effective in controlling lice, keds, mites, fleas or the like, but particularly nuisance fly on cattle. Water may be present (by weight per unit volume of solution) in an amount of 5 - 30J-, preferably 10 - 25 , more preferably 12 - 0 w/v.

Examples of organic water-miscible cosolvent include one or more of the following, separately or as a mixture of two or more thereof: alkanols, alkoxyalkanols, alkoxy-alkoxyalkanols, dipolar aprotic solvents such as dimethylsulphoxide (DMSO) or dimethylformamide (BMP) and t e like.

It is preferred to use one or more alcohols of the formula ( V ) :

HO (CH ₂ CH ₂ 0) _m R (V) wherein m - 1, 2 or 3 and R « (C C^)-alkyl.

It is more preferred to use one or more alcoholp wherein m » 2 and most preferred to use 2-(2-butoxyethoxy):ethanol, also known as diethylene glycol monobutyl ether (DGBE), which we have found well tolerated by animal skins or hides. Component (iv) may comprise at least 50$ by weight, preferably 80$ or more of DGBE.

Provision is made for the optional presence of one or more water- immiscible organic solvents. The said solvent may itself be a mixture of solvents such as the commercial Solvent comprised almost entirely of aromatic hydrocarbon fractions b.p.186-205 C sold as Shellsol AB. This commercial solvent is preferred and comprises 35$ C _q -fraction, 49$C- ₀ -fraction, 9$ C ₁ ..-fraction and 7$ napthalene and methylnaphalene. The inclusion of water-immiscible solvent, such as C_- or higher aromatic hydrocarbon(s) may enhance skin penetration of the salt(s) (i) whilst retaining the components in solution, avoiding precipitation. Alternatively or additionally a monoterpene solvent such as eucalyptus oil may be included in the formulation. Component (v), when present, may be in a proportion of (by weight per unit volume of composition) 1 - 30$, preferably 5 - 30$, more preferably in the range 10 - 25$ w/v of the carrier system.

Preferred compositions contain levamisole hydrochloride (and/or phosphate) high-cis permethrin, 2-(2-butoxyethoxy) ethanol, water with or without aromatic hydrocarbons.

We have surprisingly found that such compositions containing anthel- mintically effective amount of (i) and insecticidally effective amount of (ii) according to the invention may retain the salt(s) in solution, and im _p rove penetration of the anthelmintic salt into the animal's circulatory system through the skin barrier. SUBSTITUTE SHE

Furthermore, the carrier system may be at least as acceptable as use of DGBE alone in the sense that skin irritation in the present compositions may be no worse than and possibly better than pure DGBE solvent. 0 In order that the invention may be illustrated the following non-limiting examples are presented together with comparative tests. The figures correspond to grams per lOOmls of composition (%w/v) Example 1

The following parasiticidal pour-on composition (solution) was /O prepared: levamisole hydrochloride 11.8 g

High-cis permethrin 4,0 g water 20 g

DGBE 43 g S' Shellsol AB 20 g

This was found to control at least nuisance fly and helminths in cattle applied as a pour-on along the backline of the animals. Example 2

The following parasiticidal pour-on composition (solution) was «2θ prepared: levamisole hydrochloride 11.8 g high-cis permethrin 4,0 g wat er 15.0 g

DGBE 69.0 g

Example 3

The following parasiticidal composition (solution) was prepared and effectively used on cattle : levamisole hydrochloride 11.8 high-cis permethrin 4»0 g

DGBE 48. g water 15. g

Shellsol AB 20. g

Example 4 The following parasiticidal composition (solution) was prepared and effectively used to control helminths and sheep lice : levamisole hydrochloride 8.0 g cypermethrin 4-0 g

DGBE 44. g water 12. g

Shellsol AB 30. g

Example 5 (Comparative)

The following non-pyrethroid containing compositions were prepared and used as a pour-on for cattle : (A) (B) levamisole hydrochloride 11.8 g 23.6 g water 20. g 25. g

DGBE 40. g 58. g

Shellsol AB 20. g

w ' . £ _ U . n _t ^" _- _-___£_-. 1

Results :

The pour-on compositions of examples 1 to 3 inclusive were found effective in controlling cattle nuisance fly and helminths. The pour-on composition of Example 4 was found effective in controlling helminths in and lice on sheep. The pour-on compositions of comparative Examples 5 (A) and 5 (B) were not found effective in controlling helminths in cattle despite the presence of a levamisole salt. In the absence of a pyrethroid the effect against ectoparasites was not monitored. In all of the tests no significant skin irritation or damage to the animal skin, fleece or hide was observed.

The compositions of Examples 1 to 3 showed significant improvement in anthelmintic activity whilst Example 4 ^wa s not compared. The levamisole salt component penetrates cattle skin, in in vitro testing equipment, at a rate comparable to a commercial levamisole free base product consisting of 20$ levamisole base-in solvent DGBE. Comparative formulations of Example 5 ( ^A ) and 5 (B) demonstrated little, if any, anthelmintic activity. The pyrethroid component thus appears to synergise the activity and/or penetration of the levamisole salt. By incorporating water in the compositions there are advantages of economics, environmental considerations, reduced toxicity and flammability.

SUBSTITUTE SHEET